PROJECT ABSTRACT The effects of drinking alcohol within recommended limits on risks of CVD, diabetes, and related diseases are perhaps the most important questions yet to be answered in the fields of alcohol, nutrition, or prevention. Approximately half of all adults worldwide report current or former alcohol consumption, and the benefits or risks that alcohol poses to their health urgently need clarification. Epidemiological studies have consistently found that alcohol intake within recommended limits is associated with lower risk of coronary heart disease, ischemic stroke, and diabetes, yet no long-term randomized trial of alcohol consumption on risk of any chronic disease has yet been performed. In direct response to PAR-16-363 (Multi-Site Randomized Controlled Clinical Trial Research Center on Alcohol's Health Effects), we propose a worldwide, six-year, balanced-design randomized trial, comparing the effects of one standard serving (~14 grams) of alcohol intake daily to abstention on risk of CVD, diabetes, mortality, and related outcomes among 7,800 adults at above-average cardiovascular risk worldwide. To maximize feasibility and reflect actual use most closely, we propose to test alcohol consumption per se to abstention and thus to offer participants flexibility in their choice of beverage, while employing novel and intensive yet efficient methods to monitor safety. The Primary Specific Aim of this trial is to determine the effects of 14 gm of alcohol intake daily compared with abstention on risk of major cardiovascular events or death (myocardial infarction, ischemic stroke, hospitalized angina, need for revascularization, or death) over an average of 6 years of follow-up among 7,800 adults aged ?50 years with estimated 10-year CVD risk ?15% or prevalent CVD >6 months prior to enrollment. Secondary Aims will test the effects of alcohol on risks of incident diabetes and major cardiovascular events. Tertiary Aims will test risks of hard cardiovascular events and progression to impaired fasting glucose. Similar to other large randomized trials, we will establish ~16 centers worldwide using a stepped approach, with a 9-month vanguard phase among 7 centers in the US, Europe, Africa, and South America (in this application), followed by a second wave of additional sites to complete enrollment. Participants will be monitored for safety in multiple complementary ways, including brief electronic real-time reporting and validated yearly instruments and laboratory measures. We have brought together highly successful groups in the US and Europe to establish clinical, data, and biospecimen coordinating centers, our field centers include many of the most experienced clinical trialists anywhere, and our group has strong working relationships with NIAAA and other NIH staff necessary to ensure seamless collaboration during a U10-funded cooperative research endeavor. In this application, we propose the first randomized clinical trial of alcohol consumption, aiming to determine whether it increases or decreases the risk of CVD and diabetes among adults at above-average cardiovascular risk worldwide.